Adducts of 3-substituted-9, 11-oxido-5, 7-pregnadien-20-ones



Patented Oct. 13, 1953 UNITED STATES PATENT OFFICE ADDUCTS OF 3-SUBSTITUTED-9,11- OXIDO- 5,7-PREGNADIEN-20-ONES Robert H. Levin,

George B. Spero,

A Vern McIntosh, Jr.,

to The Upjohn Com corporation of Miehi N Drawing. Application August 5,1950, Serial No. 177,966

7 Claims. (01. 260239.55)

The present invention relates to adduets of 3-substituted-9,ll-oxido-5,7-pregnadien ones with certain dienophilicacids, anhydrides, and esters, and to a process for the productionthereof. The present application is a continuation in part of ourprior-filed copending application Serial 121,224, filed October 13,1949.

The compounds of the persent invention may be represented by thestructural formula:

of hydroxy and an acyloxy group of the formula atoms, inclusive, in theesterifying group.

It is an object of the present invention to provide a novel group ofcompounds which are useful in the preparation of steroid compoundscontaining an oxygen atom at carbon atom eleven. Another object of theinvention is the provision of a process for the production of the novelcompounds, adducts of 3-substituted-9,11-oxido-5,7- pregnadien-20-ones.Other objects of the invention will become apparent hereinafter.

The compounds of the present invention, as

thereof, which oxygenated steroids are known to have biological eflectsdiffering markedly from the unoxygenated steroids. It is, therefore, ofimportance to investigate the emphasized by the acute shortage ofadrenal cortical hormones,

and the absence of any present suggestion for alleviation of the saidshortage except through organic synthesis.

wherein R represents hydrogen or the organic residue of an alcohol. Suchesters include the atoms, inclusive. Alternately, the adduct may bedepicted by the graphic formula:

which is representative of the maleic anhydride adduct.

The compounds of the invention are usually colorless crystalline solids,which are soluble in ether, halogenated hydrocarbons, acetone, ethylacetate, and benzene. The acid anhydride adducts are readily convertedto the free S-hydroxy acid adduct by hydrolysis. These acid or anhydrideadducts in turn are readily converted into diester adducts byesterification with conventional reagents such as the diazoalkanes'[wilds et al., J. Org. Chem. 13, 763 (1948) 1. Conversely, the diestersmay be hydrolyzed to the dibasic acids which in turn may be. convertedinto their corresponding anhydrides either by heat alone. or preferablywith a mild dehydrating agent such as acetic anhydride and the like.

The 9,11-oxido compounds of the present invention are prepared by theoxidation of a 3-hydroxyor 3-acyloxy-5,l,9(11)-pregnatrien-20-one adductSing an organic peracid or concentrated hydrogen peroxide as theoxidantwhich may be used include peracetic, perpropionic, perbutyric,perbenzoic, monoperphthalic (Orth-HOOCC6H4COOO 1), and many others. Thestarting 3-hydroxyor 3.-acyloxy-5,'l',91(1-1) pregnatrien-20-one adductshave the formula:

wherein. A and B have the values stated above for the 9,11.oxido.compounds.

The adducts are conveniently prepared by the selective oxidation of anmoi ester of an adduct of 3-acyloxybisnor-5,'l,9 (I1) -cholatrien-22-al,represented by the formula:

wherein A and B have the values previously given, Bin this caseexcluding the free hydroxyl group.

Adductsv of 3,22-diacyloxybisnor-5,'l,9(11).,20- (22) -cholatetraenes[22-enol esters of 3-acyloxybisnor-5,'7 ,9 11) -cholatrien-22-alsl areconveniently preparedv by subjecting an adduct of a 3-acyloxybisnor5,'7,9(ll) -cholatrien.-22-al, 0f the formula:

CHa

l (EH-CEO Peracids.

3-acyloxy-5,'7,9 11) -pregnatrienone wherein A and B have the valuespreviously given, to the action of an acid anhydride or an acid halidein the presence of an alkaline salt of the acid. The starting adducts ofB-acyloxybisnor- 5,7,!)(11) cholatrien-22-als can be prepared fromadducts of 3-esters of dehydroergosterol by selective oxidation asdescribed and claimed in the copending application Serial 111,100 ofRobert H. Levin, filed August 18, 1949 and as more fully describedhereinafter.

The. 3-esters of dehydroergosterol, from which the3-acyloxybisnor-5,7,9(11) cholatrien-22 al adducts are prepared, can besynthesized in several ways starting with ergosterol. For example,

. ergosterol can be. transformed to dehydroergosterol with mercuricacetate according to known methods [Windaus et al., Ann. 465, 15"!(1928)] and the Zi-hydroxy group of the dehydroergosterol acylated byknown procedure. Alternatively the 3-hydroxy group of ergosterol can beacy-lated prior to the preparation of the dehy-dro derivative, aprocedure which is particularly preferred; in the preparation of the3-acetoxy derivative. The adducts. of dehydroergosterol are then.prepared by the. addition of maleic anhydride or the. like todehydroergosterol or a 3-ester thereof according to. known methodslflonigmann, Ann. 508, 89 (1934). l... The anhydrides can then be.converted to their corresponding acids and esters if desired.

The ester group, when present in the 3-position of dehydroergosterol, isfor the purpose of protecting the 3-hydroxy group in subsequent chemicalreactions. For this purpose any convenient ester of an organiccarboxylic acid, which is nonreactive under the conditions, of thereaction, is suitable. The preferred acids are the fatty acids such asformic, acetic, propionic, butyric, valeric, hexanoic, heptanoic,octanoic, decanoic; dibasic acids such as malonic, succinic, phthalic;cycloaliphatic acids such as cyclopentanoic and cyclohexanoic; andaromatic acids such as benzoic,

toluic', naphthoic, and the like. The acids may also containsubstituents such as halogen, alkyl, the methoxy radical, and the like,and these substituents will be carried throughout the synthesis. Ifdesired, the acyl group can be changed to another acyl group bysaponifying the ester to give a B-hydroxy compound, which can then bereesterified as previously described.

A preferred method for preparing some of the dehydroergosteryl adductscomprises the saponification of 'a B-acyloxy adduct of dehydroergosterolwith dilute alkali followed by acidification. The 3 hydroxy dicarboxylicacid thus formed can be converted to the 3i-hydroxy' anhydride by heat,or it can be converted to any desired B-acyloxy anhydride adduct byheating under reflux with the appropriate acid anhydride or chloride inpyridine solution. Dialkyl esters ofthe previously mentioneddicarboxylic acid adducts can be prepared by subjecting the acid to theaction of an esterification reagent such as a diazoalkane [Wil'ds etal., J. Org. Chem. 13, 163 (1948)], e. g., diazomethane, diazoethane,diazobutane, and the like.

The, selective oxidation of an adduct ofdehydroergosterol, or a 3-esterthereof, to produce an adduct of 3-hydroxybisnor-5,'7,9(I1)-cholatrien-22-al, or a 3'-ester thereof is accomplished by dissolving thedehydroergosteryl adduct in a suitable solvent, cooling to about minustoplus 30 degrees centigrade, and passing ozone intothe solution untilabout -to 1-.25-moles' of ozone per mole of adductha-ve been absorbed.The tem- D'erature of the solution should be maintained anhydride, asuitable temperature control, such below plus 30 degrees centigrade,preferably beas 100-150 degrees centigrade, must be used. since tween atemperature of minus 30 and minus 70 the adduct otherwise tends todecompose in the degrees centigrade, durin the addition of ozone, highertemperature range. If a. B-hydroxy aldealthough temperatures as low asminus 80 and as hyde adduct is thus reacted with an anhydrlde,

chloroform, acetic acid, carbon tetrachloride, p for most P p e u Wh chca be further ethylene chloride, methylene chloride, and the pu ified byrecrystal iza on f om elDne-Water,

1ike,ca be sed, acetone-pentane, or like pairs of solvents, if

The ozonides are then decomposed under redesiredducing conditions, thatis, in the absence of oxi- The ezemzetlen of the thus-prepared enoldlZlng agents, whether added or formed in the eeylete to prepare jpnacourse f the reaction by products of decompositr1en-20-one adductsinvolves dissolving the enol tion of the ozonide 'I'his means excess 651161 in a suitable solvent, cooling to about minus accomphshed decomposng the zomde n g1a The of Ozone to the double bond is cial acetic acidby the addition of finely-powdered 50 mpld that only a Small amount ofOzone mm escapes from the reaction mixture, and the As is conventionalwith ozonizations when conamount of 020116 Ordinarily q d h fo e ductedin solvents, other than glacial acetic acid, so closely eppreximetes thetheoretical amount. the solvent used for ozonization is replaced, after088 i solveilti if 9 Occurs, must be complet on of t ozomzatmn, by addng glacial taken into consideration in calculating the acetic acld andremovmg the lower bomng so1v amount or ozone to be introduced Thetemperaacetic acid, if desirei degrees centigrade, during the additionof ozone, After decomposition of the azonide and removal althoughtemperature? as low as m eighty f he Zinc the aldehyde can be recoveredby and as high as plus thirty degrees centigrade are luting the aceticacid with water, or in other con- Operative? The lower temperatures ofthe range aldehyde derivative g t dinitrophenylhy the adduct with a bathof SOlid carbon dioxide in drazone. acetone or the like, althoughvarious other meth- Adducts of 3,22-diacyloxybisnor-5,7,9(11),20- Ode ofeeellne may be m d M pf the (22)-cholatetraenes [22-eno1-esters ofadducts of cusmmary Solvents used 111 oeemzetwne Such as 3 acyloxybisnor519ml) cholatriemmfils], chloroform, methylene chloride, ethylenechlocan be conveniently prepared by heating the cori carbontetrachloride, W acid, m the responding 3-hydroxy or 3-acyloxy alde11KB, can be used for the ozonization reaction. maleic acid, maleic acidanhydride, or maleic acid The 20:22 Ozomdes m produced are thencarboxylic acid anhydride in the presence of a for decomposition of suchcompounds. This can anhydride but other anhydrides, such as metal suchas silver, platinum, or palladium in a cations is well established inthe art [Hill and also be substituted by non-reactive groups, such ashalo, alkyl, and methoxy, as in the case of chlor- Kelly Orgamcchemlstry Page The Black acetic, ortho-toluic, or methoxybenzoie acidanhydrides. The reaction can be conveniently followed by observing thecolor changes in the reac- 65 tion mixture, optimum yields beingobtained by discontinuing the application of heat when the color of thesolution changes from yellow to brown. Ordinarily the reaction is heated,at about 140 degrees centigrade for from about four to six hours, buttemperatures as low as and placed as high as degrees centigrade are alsooperaadding glacial acetic acid tive. The reaction is usually conductedat the lower-boiling solvent by fractional distillation, or boilingpoint of the anhydride, but in the case the solvent can be removed bycareful warming of the higher-boilinganhydrides, such as benzoic 75under reduced pressure prior to the addition of man Organic Chemistry,second edition, page 636, John Wiley and Sons, New York (1943); Long,Chem. Reviews 27, 452-454 (1940) As is conventional with decompositionof assumes a F acetic .acid-;.if .desiredzz. After;deoompositionmf:the.:20 :.22';ozonide;and: removal ofthe-ametal, the: ketone can .berecoveredzbye diluting; the acetic: acidixvith water, or: by otherconventionar pro cedure'tfori'the recovery oizketones; .suchasiby, 5'.

formation of:.acarbonyl: derivative, .e: g.; the 2,45dinitrophenylhydrazone; Recrystallizationifromz aeetoneor the. likeiresults in a. more highly purie fiedzketone product; The. 3 -hydroxy:ketones are prepared: by saponiflcationi" Ofl then 3eacyloxy1l0 group,to 'give the 3 -:hydroxyketone .diacid, which: Canib converteditoi theanhydride .or. .a-zdiesten: ifidesiredx. The 3-:acyloxydiaci'dsareprepared-by1i the careful reaction .of the '3-acyloxyanhydrides with :two molecular :equivalents of .alkalit.

The preparation of 3-hydroxyor 3-acyloxy:- 9,11 eoxido-SJI=pregnadien--one adducts of I the present invention; as statedpreviously; involvestheoxidation of the corresponding 3t-hydroxyl or3'"acyloxy-5,7,9 (11) -.pregnatrien-20-'one using an organicperacidorconcentrated hydrogen peroxide as the oxidant. Hydrogen peroxide isusually employed in the form of-Ja twentytoninetya-percent by weightaqueous solution;- a:

thirtypercent-solution being preferred. Theme 1 action: is carried outby stirring the adduct and oxidant together, preferably in an organicmedium which is non-reactive under :the reaction conditions. Suitable.media includechloroform;

carbon tetrachloride, mixtures of ether and BO chloroform-glacial aceticacid, and many others.- Il'ie ratio of 'oxygen furnishing agent tosteroid can -b'e varied'considerably within broad ranges; Ratios of uptotwenty moles to one are-operative,

b'ut ratios of from one to four mole's per mole of steroid areprefer-red for attainment "of optimum yields,'the exactratiobeingpreferably varied inversely with'the reaction time desired tobe em' ployed.' The temperature-of the-mixture is usually maintained atfrom about zero degrees to 40 about degrees Centigrade fora'suitableperiod, e.'-g.',' from about one-half to twenty-four hours,"depending on the concentration of oxygen-fun nishing agent, and "the9,11-oxido compoundthen' isolated in any convenient manner; such I as byvola'tilizing the reaction-medium; extracting the residue-withchloroform; filtering, volatilizmg the j chloroform, and recrystallizingthe residue,e.z g., irom eighty per cent aqueous acetone.Alternatively,' th'ecompounds may be recovered by' pouring *the'reactionproduct into water; filter ingthe solution; anddrying the precipitate.The 9;'11'-oxido compound is usually obtained "in' a state of highpurityafter "one 'Ol'ltWO recrystal lizations. A convenient reaction. mediumwhen the oxidant-is hydrogen peroxide is glacial acetic acid, and; whensuch 'is. employed; the. 9,1loxido compound is separated readily bypouring the reaction product onto cracked ice to precipitate the,9;ll-oxido compound; filtering, andrecrystallizingthedriedicrudeproduct, e. g., from. ethyl,- acetate.

The-following examples are illustrative ofl the process andproducts ofthe present inyention, but. arenotto be construed as limiting.

PREPARATION -1.DIMETHYL MALEATE 'ADDUCT or DEHYDROEBGOSTERYLLBENZOATE Toa solution. of 21 grams ofdimethyl .maleate.

adduct of. 'dehydrloergosterolin 69...mi11iliters.oi 7o adduct 20"-acetone; There wascthusiobtainedazfiAzgramsrotc dimethyl :maleateadducts or dehydroergosteryl bienzoatez melting. at 303 to20fiidzdegreesscentierade;

PREPARATIONZLDTMETHYL" MA'LEATEADDUCT"'OF. DEHYnRoEReosTERYL 'Aoarn'rmIn. a..manner essentially that... described in,Preparationsl,..the--,dimethyl,lmaleate adduct oi; dehydroergosterylacetate, .melting at 17.7 itorl79ll degrees centigrade',.wasprepared..,from the sdi methyl ,maleate .adduct.oi.dehydroergosterolandi acetyl chloride.

DEHYDROERGOSTERYL FoRMATE A solution" of six grams of -dimethyl =-maleate adduct of dehydroergosterol in fifty milliliters of 87 percentformic acid-was heated under" reflux for one hour; cooled; andthedimethyl mal'ea'te adduct of dehydr'oergosteryl formate filteredtherefrom. Upon-- crystallization from acetonep the purified materialmelted at 17715- to 178.5- degrees centigrade.

PREPARATION 4r.-M ALEIC ACID ADDUGT on:

- DEHYDBOERGOSTEBOL...

Arsolut-i'on; c11 2 .'0';grams of sodiumchydroxidedne twenty millilitersof water was added to a some.- tionrof 1.73 grams :orthe maleieanhydride adduct of dehydroergosteryl' iacetate:'-.(M:..B;- 23092323165grees; centig'rade); in forty ;millilit'ers :ofIdioxanea-s The mixturesolidified;but1dissolvedrlorr-iadditiom of 300 milliliters ofwater:andiheatingrtoxeightya degrees centigrade. After :half tans-hourthe =solu-:

, tionwascooled andimadelacid with aqueousthreee normalhydrochlorieacid; to giveslrii grams of precipitate. Oncrystallizationziromiaadioxanee water mixture- :themaleicacid-*adduct-of dehydroergosterol' melted cat r-192' degreescenti'gradeuPREPARATION 5.-.-MALE1o ANHYDRIDE ADDUor 10F-3-HEPTANoYLoxY=DEHYDRoEeeosrERoL l The maleic acid adduct ofdehydroergosterol-t from Preparation:ewes vdissolved inia mixture ="ofseven milliliters :of l-ewarmspyridinez-andrf ourteen:

' 7% milliliters otheptylic anhydride, andthe mixturezheated-:undenIefluX i or :one-houn- About eighty; percent of the-,-.reaction solvent-:wass removed; under reduced. pressure; and .theresidueltheni dis.-.- solvedaine methyl .-alcohoL-.- Thesmethylualcohols solution. was ,concentratedr. andscooledatovyield.4.8.. grams of the. maleiceanhydride adduct eon,3eheptanoyloxydehydroergosterol melting at 186-19 1 .5; degreescentigrade.

., PREPARATION (ire-Dilemma- ANEYDRIDE Aonucror'-'3-' A* solution of"535 grams of 'the maleic. anhy-r drideadduct-iof *3beta-acetoxydehydroergosteroL in 107 milliliters of methylenechl'oridewas cooled to"about-minus seventy degrees oentigradefland; ozon-ized'unti1'=505"milligrams :of ozone had been: absorbed: The temperature of."th'e solution was. then gradually raised to about "plus ten tofiftieem degrees *centigradezwhereupon seventy millilitersof glacialacetic acid. was added and the methyl-l ene chloride removed funder'reduced pressurer Seven gramsof zinc dust "was .then addedfto. the. cold*solution at' aiuniform :rate. over aaperiod iof ten minutes;while'keeping jth'e reactiontemper.-

,-aturebelow plus" twenty degreescentigrade;

After being stirred =iorfifteen minutes; the 'mixturez-was :filtered andthe 'filtratep'oured into-warter: Tlfereawase: thus obtained" 4-531grams" of maleicranhydridei: adduct of -""3 beta acetoxybis der whichmelted To a solution at 187-197 degrees centigrade. of 0.30 gram of themaleic anhydride adduct of 3 beta acetoxybisnor- 5,7,9(11)-cholatrien-22-al, in thirty milliliters of ethanol, was added twentymilliliters of alcohol containing one percent 2,4-dinitrophenylhydrazineand three percent concentrated hydrochloric acid. The mixture wasallowed to stand for one hour at room temperature and then placed in aof chloroform and alcohol, to give the ZA-dinitrophenyl hydrazone of themaleic anhydride adduct of B-betaacetoxybisnor-5,7,9 (11)-cholatrien-22-al, melting at 269-271 degrees centigrade.

PREPARATION 7.-MALEI ANHYDRIDE ADDUCT or 3- BETA-ACETOXY-BISNOR-5,7 ,911) -CHOLATRIEN-22-AL A two-liter, round-bottom flask was charged withfifty grams (0.93 mole) of dehydroergosteryl acetate maleic anhydrideadduct and one liter of methylene chloride. The solution was cooled toDry-Ice temperature with a trichloroethylene bath producing about 36milligrams of ozone per minute). The flow of ozonized oxygen wasmaintained of zinc dust. tions ture maintained at seventeen to twentydegrees centigrade. After addition, the mixture was stirred for anothertwenty minutes and then filhad been drowned out. cooled in therefrigerator The yield of crystalline product was 42 grams, assaying89-95 percent of the desired aldehyde.

PREPARATION 8 In a manner essentially that described in Preparation 6,the following compounds were prepared.

(1) Maleic anhydride adductof3-beta-formoxybisnor-5,7,9(11)cholatrien-22-al, melting at 95-130degrees centigrade. ZA-dinitrophenylhydrazone, melting at 165-168degrees centigrade.

2) Maleic anhydride adduct of 3-beta-heptanoyloXybisnor-5,7,9(1l)cholatrien-22-al, melting at 197.5-199 degrees centigrade.2,4-dinitrophenyihydrazone, melting at 253-257 degrees centigrade.

(3) Dimethyl maleate adduct of 3-betabenzoyloxybisnor5,7,9(11)-cholatrien-22-al, melting at 183-187 degrees centigrade.ZA-dinitrophenylhydrazone, melting at 224-249 degrees centigrade.

(4) Dimethyl maleate adduct of B-beta-acetoXyblsnor-5,7,9(11)-cholatrien 22 a1, melting grees centigrade.

2,4-dinitrophen- 244 degrees cen- PREPARATION 9.DIMETHYI. MALEATE ADDUCTOF 3- HYDROXYBISNOR-5,7,9 11) -0H0LATRIEN-22AL A solution of 2.69 grams(.005 mole) of the dimethyl droergosterol, 1n eighty milliliters ofmethylene chloride, cooled by a Dry-Ice and trichloroethylene bath, wastreated with ozonized oxygen until mole) of ozone was abadded and themethylene chloride removed in vacuo. While cooling in a water-bath atfifteen degrees centigrade, four PREPARATION 10,-MALEI0 ANHYDRIDE ADDUCTor 3- BETA-ACETOXY-ZZ-ACEIIOXYBISNOR- 5,7,9 (11) ,20 (22) GHOLATETRAENEA mixture of twenty grams of the maleic anhydride adduct of 3 betaacetoxybisnor- 5,7 ,9(1l) -cholatrien-22-al,

grams of the maleic anhydride adduct of 3-betaacetoxy 22 acetoxybisnor5,7,9(11),20(22)- cholatetraene, which melted at 186 to 193 de-Recrystallization of the crude product from a mixture of acetone andpentane raised the melting point to 200.5 to 202 degrees centigrade.

:aeamec "311 PREPARATION '11 In a manner essentially thatdescribedin'Prepar atio n 10,..the following compounds were pre- 1' pared.

.(1) 'The benzoyloxy 22 dimethyl maleate adduct of.'3.-betaaceoxybisnor5,7,9 (11 ),20v(.22)

cholatetraene, which melted at 210ito'2111,de

' rees .centigrade.

2) The dimethyl maleate adduct .acetoxy '22 acetoxybisnor"cholatetraene, which melted at'181 to 183' dejjgrees centigrade.

In "i the ,same manner ."'22,-acyloxy, e. g.,: formoxy,

hexanoyloxy, heptanoyloxy;

'butyroxy, valeroxy,

octanoyloxy, benz-oyloxy, like 3 acyloxybisnor ,as given above, acetoxy,propionoxy,

naphthoyloxy, and the 5,7,9 (11) ,20(22) '-chola- .tetraene,.adducts,,are obtained from the.compounds-.ofjPreparations 6,]7,..and.8..Such representative compounds .acetoxybisnor 5,7,9(1'1) include3-formoxy-22-' ,20(22) cholatetraene,

- 3&131Opl0l'l0XY-22-ECGtOXYblSIlOF-QIQ (11) ,20'(22) .cholatetraene,3,2Zedipropionoxybisnor-Bfl ,9 (11) -i20(22) cholatetraene,3,22-dibenzoyloxybisnor- .5;'1.,9'(11);20(22)-cholatetraene, and3-heptanoyl- :oxy -..22. octanoyloxybisnor 5,7,9(11)f,20'(22).zcholatetraene .adducts with maleic. anhydride. or

--,;maleic.acid esters such as theidirnethyl maleate,

v-;;dieth'yl .maleate, .idipropyl maleate, Ldiisoprop'yl umaleate,:dibutyl maleate, .dioctyl maleate,. di- 1' benzyl maleate, and thelike.

PREPABAEIoN. 12.--MALFJIC ANHYDRIDE Aonocr. or; 3- BETAyACETOXY-fiflfi(.11) rPREGN ATRrEN-fZO-om .iA .solution of 5.08 grams. of the maleicanehydride adduct of 3 -beta acetoxybisnor- 35,19 ('11)-'cholatrien.-22-al enol acetate in -100 cmilliliters .of methylenechloride was cooled to .aabout'iminus seventy degrees centigrade and."sozonized until483 :milligrams of ozone had been .fiiabsorbed...Fifty-milliliters of glacialxaceticacid was thenadded and themethylenechloride .re-

' .movedunder' reduced, pressure. 'An: additional "thirtywmilliliters ofglacial.

-;added ,and the; ozonide.

rsevenzgrams of-zpowdered aceticuacid was: then decomposed :rby addingz-inc at a substantially tuniform rate -;while imaintaining .ithe'reaction temperature between-seventeen and twenty deqgreesccentigrade."The mixture a was: stirred I for an; additional twentyt'minutes;filtered, and the :zincvwashedswith 140 milliliters otiglacial aceticacid. The: organic extracts werezcombinedand diluted with seventymilliliters of water. When --.crystallization commenced; the rate ofprecipittation was increased-=-by addition or two volumes of water. ofth i There was thus obtained "4.0"grams maleic anhydride adduct of 1B-beta- ..acetoxy-,5,7.,9(ll).epregnatrien -.20. -;one, which lmeltedat240 130 2645 degrees centigrade. Sev- -eral recrystallizations of thecrude .material from vacetone raised, the melting point to- 263.5to264.5

i degrees centigrade.

PREPARATION 13.-,1VIALEIC' Aorn Annuo r or 3-BETA 'HYDRoXY-5;7;9 11-1REGNATRIEN20-ONE ."A' solution ofiifizpgrams (O;0l00.:mole):of thermaletic -anhydride adduct :of 3-,beta-acetoxyone, TM. P. 263-.-264.5

I degrees centigrade; Vina-mixture of 100 milliliters l ,4,-dioxane .and.400, milliliters ,of water con-" (0.lO'm0le)-,.of sodium hya oxideawas.allowed-to. stand-at room tempera- ..ture. iorx two and one-half hours,whereupon a small quantity of plate-like crystals formed.

These were dissolved by heating the mixture to seventy-ridegrees "fiftymilliliters of 312 centigrade for onee'ha'lf 2 hour. Thereaction-mixture was then madeaacidswith three normal hydrochloric. acidand refrigerated to give a:precipitateaOfJBDS grams of needle-like,crystals meltingati 173477 degrees centigrade.

On crystallization :7 from :..-a

ddioxane-waterv mixture, the compound meltedzat 1.521 1-215 i degreescentigrade.

Thev melting point wasf-foundl to vary somewhat-with the rater -ofheating.

Analysis:

"Calculated fQfCgHQO .10; 70.07 ;:H;17;53 Found 69.80;:'H,-,7. .47PREPARATION 14.--DIMETHYL lVIALEATE OF'53;BET-A- HYDROXY-5,7 ,9 (11)-PREGNATBIEN20ONE A suspension of 0.4 gram of the maleic acid adduct of:3-beta-hydroxy-5,7,9 (11) -tpregnatrien- ZO-onen'nfifty milliliters ofdry ether, was cooled win an ice-salt bath while a slight excessofdiazo- 1121 minute period. with after additionwas complete, thesolution was methane in methylene chloride was .addedover stirring. Tenminutes -:-placed on a steam bath and concentrated rapidly grees..centigrade. recrystallization, the

192-197 degrees centigrade.

. tanoyloxyl-.5,7,9(1l) hydroxy -5,7,9

. precipitate was. collected The residue was crystallized from give0.34g-ram; of

to. dryness. :an acetone-wateremixture to .the' dimethyl maleate of3beta-hydroxyi-5,'l,9

(Ill-pregnatrien-Zflmne, melting at 193-195. de-

After chromatography and compound melted at Inthe. same manner asgivenabove, otherwdialkyl maleates, e. g., the diethyl .dipropyl,..di-

isopropyl, dibutyLanddiootyl maleates, of 3-.-hydroxy-5,7,9(1l) paredfrom 3-hydroXy-5,'l,9.(l1)

, one maleic acid adduct and -,pregnatrien-20-one .are .pre-.-pregnatrien.-20- the appropriate -.diazoalkane,-. or. by otherequivalentv esterification procedure.

PREPARATION' 15.MALEIo ANHYDRIDE ADDUCT or" 3 -BErA-HEPTANoYLoxY-5fl ,911 )rmseN ATRIENQO-QNE The. .maleic .anhydride adduct of 3-beta-hep--pregnatrien-20-one, melting .point.170.1'7l. degrees centigrade, was,prepared .-by.. refluxing the maleicacid adduct of B-beta- (11)-pregnatrien-.20-one :with hepfor a period of prod- .tylic anhydride andpyridine twenty hours,- and working up'the reaction not in theusualmanner.

PREPARATION Mir-Munro ANHYDRIDE ADDUCT or 3- BETA-HYDROXY-Efl ,9 (11)-1REGNATRIEN-20-ONE (Similarly, the maleic anhydride adductof 3-beta-hydroxy 5,7,9(11) pregnatrien -20- one, melting point about 195degrees centigrade, was

"preparedby refluxing the maleic acid adduct of .-3-beta.-hydroxy-15,7,9(l1) pregnatrien .-20-,one with Dowtherm for eight hours. The3-hydroxy- .-maleicanhydride adduct is also obtained by heatingthe3-hydroxy maleic acid adduct to just aboverits melting point, whichprocedure causes -water tobe: evolved with closing of the anhydridering.

PREPARATION 17. DIMETHYL MALEATE 0F 3-BETA- AoEToxY-5;7,9 (11)PREGNATRIEN-20ONE A solution of 0.15 gram of the dimethyl maleate adductof 3+beta-hydr0xy-5,'7,9(11) -pregnatrien- 20-one, .in. 2.5 millilitersof acetic anhydride and 2.5.milliliters of pyridine, was heated on thesteam bath for ninety minutes, cooled to room temperature, and pouredinto ice-water. The resulting .by. filtration and found tomelt at 205209degrees centigrade. .Recrystallization from methanol gave the dimethylmaloxy-5,7,9 (11) eate of 3-beta-acetoxy-5,7,9(11)-pregnatrien-20- one,melting at 207-211 degrees centigrade.

By the same manner PREPARATION 18.-DIMETHYL MALEATE or 3-BETA-AoEToXY-5,'7 ,9 11 -PREGNATRIEN-20-ONE A suspension of fifteen grams of3-beta-acetoxy-5,7,9(11)-pregnatrien-20-one maleic anhydride adduct in320 milliliters of methanol was cooled in an ice-salt bath. A boilingchip was added and the suspension treated with approximately 775milliliters of diazomethane-methylene chloride solution inIOU-milliliter portions over a period of three hours, all of the solidsgoing into solution. At the end of this time the solution was reduced toone-half its original volume on the steam bath to remove excessdiazomethane, filtered, and concentrated to about 250 milliliters. Uponcooling, crystals 3-beta-acetoxy -5,7,9(11) pregnatrien-20-one, meltingat 204-208 degrees centigrade, were deposited. The yield was 13.2 grams(87 percent of theory).

In the same manner as given above, still other5,7,9(11)-pregnatrien-20-one adducts are prepared from the corresponding3,22-diacyloxybisnor-5,7,9 (11) ,20 (22) -cholatetraene maleic acid,maleic acid anhydride, and maleic acid diester adducts. Such compoundsinclude the 3-form- -pregnatrien-20-one maleic acid, maleic acidanhydride, dimethyl maleate, diethyl maleate, dibutyl maleate, dioctylmaleate, diisopropyl maleate, dibenzyl maleate, and like adducts; thecorresponding 3-propionoxy, butyroxy,

octanoylincluding, for example, 3-propionoxy5,7,9(11) regnatrien-ZO-onedipropyl maleate, 3-benzoyloxy-5,7,9 (11) -pregnatrien-20- one dibenzylmaleate, 3-heptanoyloxy-5,7,9(11)- pregnatrien-ZO-one dimethyl maleate,3-valeroyloxy -5,7,9(11)- pregnatrien -20- one maleic acid anhydrideadducts, and the like.

Example 1. Dimethyl maleate adduct of 3-beta-(rectory-9,11-omido-5,7-pregnadien-20-one One gram (0.002 mole) of thedimethyl maleate adduct of 3-beta-acetoxy-5,7,9(11) -pregnatrienof thedimethyl maleate of degrees centigrade, [a] +11.4 degrees (inchloroform).

Analysts:

Calculated for (32 11 0.;

percent IC, 67.68; percent H, 7.44 Found percent 0, 67.74; percent H,7.35 68.02; 7.49 Example 2.Maleic anhydride adduct 0) 3-betaacetozy-9,l1-critic-5,7-pregnadien-20-one Five grams (0.011 mole) of the maleicanhydride adduct of 3-beta-acetoxy-5,7,9(11)-pregnatrien-20-one wasdissolved in milliliters of beta-acetoxy-9,1 l-oxido -5,7- pregnadien-20- one, melting at 240-246 degrees centigrade, were obtained.

Example 3.-Maleic anhydride adduct of 3-betaacetoary-QJI-oa:ido-5,7-pregnadien-20-rme A solution of fifty grams of the maleicanhyof 3-beta-acetoxy-5,7,9(11)-pregnot having a melting point of 254 to259 degrees centigrade, [alphal +33.2 degrees.

Example 4 Analyst's:

Calculated for G39H34O7 percent C, 72.43; percent H, 6.46 Found percentC, 72.62; percent H, 6.42

(2) Maleic anhydride adduct ofB-heptanoylwry-9,11-oXid0-5,7-pregnadien-20-one, M. P. 168- 169.5degrees centigrade, [alphal +26.1 degrees (in chloroform).

Analysis: I j H V Camnmeamruanao,

percent C, 71.48; percent. H,'7;69

Found percent C, 71.27; percent H, 7.43

Approximately .445 .milliliters of five percent sodium hydroxidesolution was .added -to 22.26 grams of 3-beta acetoxy 9,11-oxido5,7-pregna- "dien one maleic ahhydride a'dduct in a oneliter- Erlenmeyeriia sk, and the mixture stirred until the solid had gone -into solution.About 1 85 l liliters of ten percent hydrochloric 1 acid was then addedat room temperature or 'below, iimtil -the mixture WaS' acid" to wvhereupon the" 'hydroxy' diacid began to precipi- ,zztate. Upon coolingthe-flask overnight, filtering and air-drying "the pro'du'ct at roomtemperalture; a -yield of 19A grams oi desired- 3'-beta-hymaid adduct,melting at 229- 233 'd'egrees centigrade with decompositionjwas Iobtained. An add'itional crop-of crystals "was obtained: by concentration of: the 'mother liquor.

I'Ihe same product is obtainedby: epoxidation .cofl theit9,11f-d0ublebond of 3 -beta-hydroxy-5,7,9-

(11) -pregnatrien' 26 onetmal'eic acid adduct with fhydrogen peroxide-in the-manner of the preced- ---lng examples using a iglacialaceticacid medium.

-i i3-beta=hydroxy 9',1l=oxido=5;7=pregnadien-26- one maleic acid adduct(19.4 grams) was placed in a" vacuum *ovenandheated for ten hours at 137-140"degrees-*centigrade under -a pressure of only one-half millimeter'of'mercury. The yield ofidesired: anhydride, which melts-:at 233 to 240degrees centigrade with decomposition, was quantitative.

-The sameproduct is obtained by epoxidation .of the 9,11 .double bond of'3 beta -hydroxy- 5,7--,9(l1) -preg-natrien-20-one maleic anhydride.adduct with hydrogen peroxidexin the manner of the preceding examples,using a glacial acetic acid medium.

' Example 7 Monome'thyl maleate of 3 meta-hydressy-9,11 -oa:ido-5;7-pregnddien-20-one A solution. of 'five grams .of themaleicanhy- 'd'rideadduct ofi 3 beta-acetoxy-9,l1-oxido 5,7- 'pregnadien-zu-onein'145milliliters of methanol and a solutionof five gramsof .sodium hydroxide.in milliliters'of water were mixed and the mixture allowed to. standvfor I one. hour,'. whereaiter 145 milliliters of water was added, themixture allowed to stand forseven'hours, then made acid with threenormal hydrochloric acid and placed in the refrigerator. The mixture wasthen extracted with methylene chloride, washed with "sodium chloridesolution, and dried over sodium sulfate. The yield was 4.93 grams,melting point "136-160 degrees centigrade. After recrystalliza- "tion'three timesfrom a solution of chloroform, methanol, and ether, themelting point was 193- 198 degrees centigrade, [alpha] +l9.4'-degrees(chloroform) -.zAnat 7 sis: ifiaiculat'ed for 7,133.40;

C 68.10 percent H, 7 .47 percent OCH 6.7 6

percent Found tC 67 90 tH 714 percent OCH 622 rcen ;percen 3 W "67.97;7.35; 6.12

:The same" product is obtained by epoxidation of the 9,11 double bond of3--beta-hydroxy- Congo red paper;

. Example ty milliliters centigrade,

'sponding diacid or anhydride ate with hydrogen peroxideaccording-toithemanner of the preceding examples.

8. Dimethyl mdleate of 'B beta-MJ- dreary-9,1 1 oxido- 5 ,7Tpregnadien-ZOwne .A suspension of 0.65 gram of the monomethyl ester ofthe maleic acid adduct-of 3-b'eta"-hydroxy-9.,ll-oxido-5,7-pregnadien20-one in twenof anhydrous ether was treated'with an .excessof 'diazomethane in methylene-chloride solution. On addition ofmethylene-chloride the compoundwentintasolution, andwvas allowed tostand about two hours, the solution evaporated to dryness, and theresidue dissolved intwelve milliliters of hot ethanol,.filtered,.concentrated,-=water added, and the solution placed in therefrigerator. Theprecipitate was separated by filtration, to'give ayield of 0.54: gram, melting vat 267-'-2ll degrees centigrade. The

, product was passed over a column of alumina for purification, andthisprocedure yielded 0.50 gram of product, which upon crystallizationfrom methanol had a melting point 05216-212 degrees [alphal -l-l5xidegrees (chloroform).

Analysis:

Calculated for C HMO-I fiperclent C, 68.62 percent'H, 7.68 percentOCHa13:13 0111'! percent C, 68.62 percent H, 7.61 percent OCFL; 12.10 68.617.64; 12:22 Infra red analysis was inagreement with the structureproposed.

"The same product is obtained by "epoxidation of the 9,11 double bond of3-beta-hydroxy- 5,7 ,6 11) -pregnatrien-20-one dimethyl "maleate withhydrogen peroxide according to the 'method 7 preceding examples, or fromthe correin methan'ohby treatment with diazomethane in methylene chloofthe ride.

*9,1l-'oxido-5,7 pregnadien 20 one within "the scope of the presentinvention includeB-propionoxy 9,11 oxido 5,7-pregnadien-20-one maleicacid adduct, 3 butyroxy-9,l1-oxido-5,7 -"pregnadien-20-onemaleicanhydride adductfB-fbrmoxy -9,l1 oxido 5,7 pregnadien-ZO-onedimethyl maleate adduct, 3-formoxyi-9,11 oxido5,7-pregnadien-20-one'maleic anhydride adduct, 3'-acetoxy-9,l1-oxido 5,7pregnadien-'-=one maleic acid adduct,3 propionoxy-9,1l-oxido 5,7-.pregnadien 20-one dimethyl maleate adduct,?- butyroxy'-9,ll-oxido-5,7pregnadien-20-one diethyl maleate adduct, 3-octanoyloxy-9,l1-oxido-5,7-pregnadien-20-one dioctyl maleate adduct,- 3- benzoyloxy-9,l1-0xido5,7-pregnadien 20'-- one .maleic acid adduct, B-propionoxy -.9,11-..oxido- 5,7.-pregnadien-20-one maleic anhydride adduct, and the like,whichare prepared in the same manner as given above, by epoxidation ofthe selected 9,11-unsaturated starting compound.

In the same manner-as given for the preparation of the .anhydrideadducts, 3.-acyloxy-9',l1-

oxido-5,7-pregnadien-20-one maleimide and N- .alkyl substitutedmaleimide adducts are prepared from the corresponding 9,11-unsaturatedcompounds.

It is to be understood that the invention is not to'be limited to theexact details of operation or exact compounds shown and described asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by thescopeof. the appended claims.

1 7 We claim: 1. A 3-substituted-9,11-oxido 5,7-pregnadien- 20-oneadduct represented by the formula:

I C=O CH:

wherein B is selected from the group consisting of hydroxy and anacyloxy group of the formula AcO, Ac being the residue of anunsubstituted organic monocarboxylic acid containing from one to tencarbon atoms, inclusive, and wherein A is radical of a dienophileselected from the group consisting of maleic acid, maleic anhydride, andmaleic acid diester wherein the esterifying group is of solelyhydrocarbon nature and contains from one to eight carbon atoms,inelusive.

2. A 3-acy1oxy-9,11-oxido 5,7-pregnadien-20- one maleic anhydrideadduct, wherein the acyloxy group is of the formula AcO, Ac being theresidue of an unsubstituted organic monocarboxylic acid containing up toten carbon atoms, inclusive.

3. Dimethyl maleate adduct of oxido-5,7-pregnadien-20-one.

4. Maleic anhydride adduct of 3-acetoxy-9,11-oxido-5,7-pregnadien-20-one.

5. Maleic anhydride adduct of 3-hydroxy-9,11-oxido-5,7-pregnadien-20-one.

6. Maleic acid adduct of 3-hydroxy-9,11-oxido- 5,7-pregnadien-20-one.

7. Dimethyl maleate of 3-hydroxy-9 ,11-oxido- 5,7-pregnadien-20-one.

ROBERT H. LEVIN. A VERN MCIN'IOSH, JR. GEORGE E. SPERO.

3-acetoxy-9,11-

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,403,683 Reichstein July 9, 1941 2,530,389 Levin et a1. Nov.21, 1950 2,530,390 Levin et a1 Nov. 21, 1950

1. A 3-SUBSTITUTED-9,11-OXIDO - 5,7-PREGNADIEN20-ONE ADDUCT REPRESENTEDBY THE FORMULA: